The present invention relates to a novel series of antimalarial 1,2,4-trioxanes analogues of general formula 7,
wherein R represents cycloalkyl groups selected from the groups consisting of cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl or aryl groups selected from phenyl, 4-bromophenyl and 4-chlorophenyl, R1 and R2 represent hydrogen, alkyl group selected from methyl, ethyl, propyl and decyl, aryl selected from phenyl or parts of a cyclic systems such as cyclopentane, cyclohexane, substituted cyclohexane, cycloheptane bicyclo(2.2.1)heptane, adamantane and its preparation thereof; several of these novel compounds show promising antimalarial activity against multidrug resistant malaria in mice.
Malaria, endemic in many parts of the tropical countries, with approximately 300-500 million episodes of clinical infection and nearly 2 million deaths per year worldwide, is a serious health problem. The rapid emergence of resistance by Plasmodium falciparum to the existing therapies, e.g. chloroquine, mefloquine etc, has added new dimensions to this problem. Against this background discovery of artemisinin 1, a sesquiterpene lactone endoperoxide, isolated from the Chinese traditional herbal remedy against malaria, Artemisia annua, has been a welcome development in the chemotherapy of malaria. Some of the semisynthetic derivatives of artemisinin e.g. artemether 2, arteether 3, and artesunic acid 4 are more active than artemisinin and are currently being used clinically. These drugs are effective against both chloroquine sensitive and chloroquine resistant strains of Plasmodium falciparum [For reviews on artemisinin and its derivatives, see: (a) Klayman, D. L. Science, 1985, 228, 1049; (b) Luo, X. D.; Shen, C. C. Med. Res. Rev., 1987, 7, 29; (c) Zaman, S. S.; Sharma, R. P. Heterocycles, 1991,32,1593; (d) Butler, A. R.; Wu, Y. Lin. Chem. Soc. Rev., 1993, 21,85; (e) Meshnick, S. R.; Taylor, T. E.; Kamchonwongpaisan, S. Microbiol. Rev.,1996, 60,301; (f) Bhattacharya, A. K.; Sharma, R. P. Heterocycles,1999, 51, 1681; (g) Haynes, R. K.; Vonwiller, S. C. Acc. Chem. Res., 1997, 73]. 
The limited availability of artemisinin from natural sources and the realization that 1,2,4-trioxane is the phannacophore for the antimalarial activity of artemisinin and its analogues, has inspired major efforts towards the preparation and bioevaluation of structurally simple synthetic 1,2,4-trioxanes. As a result of these efforts, a number of metho dologies have been developed by various workers for the preparation of 1,2,4-trioxanes (prototypes of these trioxanes are given in FIG. 1). Several of these synthetic trioxanes have shown promising antimalarial activities both in vitro and in vivo [Cumming, J. M.; Ploypradith, P.; Posner, G. H. Adv Pharmacol, 1999, 37,253]. 
Singh et al. have prepared 1,2,4-trioxanes by the regiospecific photooxygenation of allylic alcohols to furnish -hydroxyhydroperoxide, which on condensation with aldehyde or ketone in the presence of an acid catalyst furnish 1,2,4-trioxane [(a) Singh, C. Tetrahedron Lett. 1990,31,6901;(b) Singh, C.; Misra, D.; Saxena, G.; Chandra, S. Bioorg. Med. Chem. Lett.,1992, 2, 497; Singh, C.; Misra, D.; Saxena, G.; Chandra, S. Bioorg. Med. Chem. Lett., 1995,17, 1913]. As an extension of this work we have prepared a new series of novel 1,2,4-trioxanes which have been found to be highly active against multi-drug resistant P. yoelii in mice and which are the subject matter of this patent. This invention relates to novel substituted 1,2,4-trioxanes useful as antimalarial agents.
This invention also relates to a process for the preparation of novel substituted 1,2,4-trioxanes.
This invention particularly relates to a process for the preparation of 6-[(cycloalkylphenyl/Substituted biphenyl)vinyl]-1,2,4-trioxanes, a new series of antimalarial agents. More particularly the present invention provides a process for the preparation of 1,2,4-trioxanes of general formula 7 wherein R represents cycloalkyl groups selected from the groups consisting of cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl or aryl groups selected from phenyl, 4-bromophenyl and 4-chlorophenyl, R1 and R2 represent hydrogen, alkyl group selected from methyl, ethyl, propyl and decyl, aryl selected from phenyl, or part of a cyclic system such as cyclopentane, cyclohexane, substituted cyclohexane, cycloheptane, cyclo(2.2.1 )heptane, adamantane. These trioxanes are new compounds and are useful as antimalarial agents. Some of these compounds have been tested against multi-drug resistant malaria in mice and have shown promising antimalarial activity. The invention, thus relates to pharmaceutical industry.
The trioxanes of the general formula 7 are new chemical entities and they have not been prepared earlier.
The main objective of the present invention is to provide novel substituted 1,2,4-trioxanes.
The objective of the present invention is also to provide a process for the preparation of novel substituted 1,2,4-trioxanes of general formula 7, a new series of antimalarial agents. Accordingly, the present invention provides a process for the preparation of novel substituted 1,2,4-trioxanes of general formula 7 as given below. 
Wherein R represents cycloalkyl groups selected from the groups consisting of cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl or aryl groups selected from phenyl, 4-bromophenyl and 4-chlorophenyl, R1 and R2 represent hydrogen, alkyl group selected from methyl, ethyl, propyl and decyl, aryl selected from phenyl or parts of a cyclic systems such as cyclopentane, cyclohexane, substituted cyclohexane, cycloheptane, bicyclo (2.2.1)heptane, adamantane which comprises reacting aryl methyl ketone of formula 1, wherein R represents cycloalkyl groups selected from the groups consisting of cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl or aryl groups selected from phenyl, 4-bromophenyl and 4-chlorophenyl with haloacetate such as ethyl bromoacetate or ethylchloroacetate and Zn in presence of catalytic amount of I2 in an aprotic organic solvent at a temperature range of room temperature to refluxing temperature to give xcex2-hydroxyester of formula 2, wherein R has the same meaning as above, dehydrating the above said xcex2-hydroxy esters of formula 2 using a catalyst selected from the group consisting of I2, P2O5, PTSA and cation exchanger such as Amberlyst-15, in an aprotic organic solvent at room temperature to refluxing temperature to obtain xcex1,xcex2-unsaturated ester 3, wherein R has the same meaning as above, reducing the above said esters of formula 3 with a metal hydride such as LiAlH4 in an ether solvent at a temperature ranging from 0xc2x0 C. to refluxing temperature to give allylic alcohols of the formula 4, wherein R has the same meaning as above, photooxygenating the above said allylic alcohols of formula 4 in presence of a sensetizer in an organic solvent at temperature ranging from xe2x88x9210xc2x0 C. to room temperature to obtain xcex2-hydroxyhydroperoxides of formula 5, wherein R has the same meaning as above , reacting in situ or after isolating the xcex2-hydroxyhydroperoxide of the formula 5 with an aldehyde or ketone of the general formula 6, wherein, R1 and R2 represent hydrogen, alkyl group such as methyl, ethyl, propyl and decyl, aryl such as phenyl and parts of a cyclic system selected from groups consisting of cyclopentane, cyclohexane, cycloheptane, substituted cyclohexanes, bicyclo(2.2.1)heptane, adamantane, in presence of an acid catalyst in an aprotic organic solvent at a temperature range of 0xc2x0 C. to room temperature, followed by isolation and purification by known methods to furnish the trioxanes of general formula 7, wherein R, R1 and R2 have the same meaning as above.
In the process aryl methyl ketone of formula 1 are reacted with haloacetate such as ethyl bromoacetate or ethylchloroacetate and Zn in presence of catalytic amount of I2 in an aprotic organic solvent such as benzene, toluene, diethyl ether, THF to furnish xcex2-hydroxy ester of formula 2.
These xcex2-hydroxy esters of formula 2 can be isolated and purified by standard laboratory methods such as column chromatography or crystallization or can be used without purification in the next step. xcex2-Hydroxy esters of formula 2 except compound 2e (formula 2, R=Ph) are new compounds and they have not been prepared earlier. xcex2-Hydroxy ester 2e (formula 2, R=Ph) is a known compound [Farmaco. Ed. Sci 1978,33(12), 992-8 (Ital)].
In the process dehydration of xcex2-hydroxy esters of formula 2 may be effected in aprotic organic solvent such as benzene, toluene, CHCl3 in the presence of a dehydrating catalysts selected from I2, P2O5, p-toluene sulfonic acid, H2SO4 or Amberlyst-15 (cation exchanger) to furnish xcex1,xcex2-unsaturated esters of formula 3. These unsaturated esters can be isolated and purified by standard laboratory methods such as column chromatography or crystallization. The xcex1,xcex2-unsaturated esters of formula 3 except compound 3e (formula 3, R=Ph) are new compounds and they have not been prepared earlier. xcex1,xcex2-unsaturated ester of formula 3e (formula 3, R=Ph) is a known compound [Chemical Abstract, 1976, 86, P106177d].
In the process reduction of xcex1,xcex2-unsaturated esters of formula 3 is effected with a complex metal hydride such as LiAlH4 in an ether solvent such as diethyl ether, tetrahydrofuran, to furnish allylic alcohol of the formula 4. These allylic alcohols of formula 4 can be isolated and purified by standard laboratory methods such as crystallization or column chromatography. The allylic alcohols of formula 4 are new compounds and they have not been prepared earlier.
In the process photooxygenation of allylic alcohols of formula 4 may be effected by passing oxygen gas or air in the solution of the alcohol in an organic solvent and in the presence of a dye and a light source which provides visible light for a period in the range of 2 to 5 h, to furnish xcex2-hydroxyhydroperoxides of formula 5. These xcex2-hydroxyhydroperoxide of formula 5 which are new chemical entities can be isolated and purified by standard laboratory methods such as crystallization or column chromatography or can be used in situ, without purification, in the next step. The dye which acts as a sensitizer i.e. converts 3O2 to highly reactive 1O2, may be selected from methylene blue, Rose Bengal, tetraphenylporphine and the like. Organic solvent used may be selected from CH2Cl2, benzene, CH3CN, acetone, ethanol and the like.
In the process reaction of xcex2-hydroxyhydroperoxide of formula 5 with aldehyde/ketones of formula 6 is done in an aprotic solvent in the presence of an acid catalyst to furnish trioxanes of formula 7. The aldehyde and ketones used may be such as benzaldehyde, acetone, ethyl methyl ketone, methyl propyl ketone, decyl methyl ketone, cyclopentanone, cyclohexanone, and bicyclic ketone such as norcamphor and tricyclic ketones such as 2-adamantanone. The acid catalyst used may be such as HCl, p-toluenesulfonic acid, H2SO4, acidic resin like Amberlyst-15. The aprotic solvents used may be such as CH2Cl2, CHCl3, benzene, CH3CN. These trioxanes of formula 7 can be isolated and purified by standard laboratory methods such as column chromatography and crystallization. These trioxanes are new chemical entities and they have not been prepared earlier. Some of the trioxanes of formula 7 have been tested against malarial parasites in mice and show promising antimalarial activity.
The invention is further illustrated by the following examples which should not, however, be construed to limit the scope of the present invention.